Papers by James McCluskey
Immunity, Jan 19, 2016
A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2(+) T... more A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2(+) T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative reactivity in a discrete subset of TRAV1-2(+) MAIT cells. This recognition was attributable to CDR3β loop-mediated effects within a consensus TRAV1-2(+) TCR-MR1-Ag footprint. Furthermore, we have demonstrated differential folate- and riboflavin-derivative reactivity by a diverse population of "atypical" TRAV1-2(-) MR1-restricted T cells. We have shown that TRAV1-2(-) T cells are phenotypically heterogeneous and largely distinct from TRAV1-2(+) MAIT cells. A TRAV1-2(-) TCR docks more centrally on MR1, thereby adopting a markedly different molecular footprint to the TRAV1...
The Journal of Immunology, Oct 15, 1996
Clustering of autoantibody specificities is a consistent finding in patients with systemic autoim... more Clustering of autoantibody specificities is a consistent finding in patients with systemic autoimmune diseases. Patients with Sjögren's syndrome frequently have autoantibodies to La, 60-kDa Ro(SS-A) protein (Ro60), and 52-kDa Ro(SS-A) protein (Ro52). In the case of anti-Ro60 and anti-La, there is evidence that these specificities occur together because of the physical association of the Ro60 and La proteins that form a ribonucleoprotein particle (RNP). Thus, the autoantibody response may spread from a single epitope to involve new epitopes located within other components of the RNP. The physical association of Ro52 with the Ro/La RNP has remained controversial, implying that Abs to Ro52 are not a consequence of intermolecular spreading and may be triggered independently of the anti-Ro60 response. To examine this relationship of the immune response to Ro52 and Ro60, mice were immunized with recombinant Ro52, Ro60, or La, and examined for autoantibody production. Immunization with Ro52 resulted in rapid, high titer Ab production to Ro52, followed 7 to 14 days later by lower titer autoantibody production to Ro60. Immunization with Ro60 led to anti-Ro60, which was also followed 7 to 14 days later by a lower titer anti-Ro52 response. Cross-reactivity of affinity-purified Abs from immune mouse sera was not observed. These observations suggest that the autoimmune responses to Ro60 and Ro52 are linked intrinsically, despite previous evidence suggesting they are not associated in vivo. The mechanism of linkage remains unclear, but the data are most consistent with some physical association of Ro52 and Ro60 allowing autoimmunization, presumably as a result of normal cell turnover or specific injury in vivo.
Current Opinion in Immunology P, Feb 1, 2014
αβT-cell mediated immunity is traditionally characterised by recognition of peptides or lipids pr... more αβT-cell mediated immunity is traditionally characterised by recognition of peptides or lipids presented by the major histocompatibility complex (MHC) or the CD1 family respectively. Recently the antigenic repertoire of αβT-cells has been expanded with the observation that mucosal-associated invariant T-cells (MAIT cells), an abundant population of innate-like T-cells, can recognise metabolites of vitamin B, when presented by the MHC-related protein, MR1. The semi-invariant MAIT T-cell antigen receptor (TCR) recognises riboflavin and folic acid metabolites bound by MR1 in a conserved docking mode, and thus acts like a pattern recognition receptor. Here we review and discuss the recent observations concerning antigen presentation by MR1, the advent of MR1-Ag tetramers that specifically stain MAIT cells, recognition by the MAIT TCR, and our emerging understanding of MAIT cells in disease.
Seminars in Arthritis and Rheumatism, Oct 1, 2000
Objectives: Rheumatoid arthritis (RA) is a chronic inflammatory disease for which immunogenetic s... more Objectives: Rheumatoid arthritis (RA) is a chronic inflammatory disease for which immunogenetic susceptibility factors have been defined. In a recent case control study, it was shown that a prior intimate relationship with pet cats or budgerigars confers risk for subsequent development of RA after a period of latency. Pets are a potential reservoir for putative microbial agents that could be a stimulus for chronic inflammation subject to the influence of immunogenetic factors. Therefore, a study was undertaken to determine whether the presence of HLA-DRB1 alleles bearing the RA susceptibility motif influenced risk for RA associated with prior exposure to pets.
Nat Immunol, 2011
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids,... more The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding
Journal of Immunology, 2006
HLA-A*31:01 is associated with carbamazepine (CBZ) hypersensitivity in Caucasian and Japanese pop... more HLA-A*31:01 is associated with carbamazepine (CBZ) hypersensitivity in Caucasian and Japanese populations. Herein, we show that HLA-A*31:01+ restricted the activation of carbamazepine-specific CD8(+) T-cells, which provides an immunological basis for the genetic association. Furthermore, CD4(+) T-cells were activated with carbamazepine in a HLA-DRB1*04:04-restricted manner, indicating that a common HLA haplotype may contribute to the multiclonal T-cell response seen in European patients with CBZ hypersensitivity.
Immunity, Dec 18, 2009
T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T ce... more T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B*0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B*4402 and HLA-B*4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B*0801, HLA-B*4402, and HLA-B*4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did not alloreact against HLA-B*4403, and the single residue polymorphism between HLA-B*4402 and HLA-B*4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes.
Nature immunology, Jan 20, 2015
While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and ... more While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1-restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib-reactive T cells, and γδ T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small-molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets.
Nature Immunology, 2015
Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide ... more Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.
Nature Immunology, 2015
Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide ... more Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.
The Journal of experimental medicine, Jan 22, 2015
Studies on the biology of mucosal-associated invariant T cells (MAIT cells) in mice have been ham... more Studies on the biology of mucosal-associated invariant T cells (MAIT cells) in mice have been hampered by a lack of specific reagents. Using MR1-antigen (Ag) tetramers that specifically bind to the MR1-restricted MAIT T cell receptors (TCRs), we demonstrate that MAIT cells are detectable in a broad range of tissues in C57BL/6 and BALB/c mice. These cells include CD4(-)CD8(-), CD4(-)CD8(+), and CD4(+)CD8(-) subsets, and their frequency varies in a tissue- and strain-specific manner. Mouse MAIT cells have a CD44(hi)CD62L(lo) memory phenotype and produce high levels of IL-17A, whereas other cytokines, including IFN-γ, IL-4, IL-10, IL-13, and GM-CSF, are produced at low to moderate levels. Consistent with high IL-17A production, most MAIT cells express high levels of retinoic acid-related orphan receptor γt (RORγt), whereas RORγt(lo) MAIT cells predominantly express T-bet and produce IFN-γ. Most MAIT cells express the promyelocytic leukemia zinc finger (PLZF) transcription factor, and t...
Blood, Jan 23, 2015
IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogenei... more IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8(+) Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORγt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNγ, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to G...
Journal of immunology (Baltimore, Md. : 1950), 1999
We investigated the consequences of altering the form and valence of defined autodeterminants on ... more We investigated the consequences of altering the form and valence of defined autodeterminants on the initiation and spreading of experimentally induced La/Ro autoimmunity. Anti-La and Ro (SS-A) Ab responses were monitored following immunization of healthy mice with defined immunodominant and subdominant T cell determinants of the La (SS-B) autoantigen synthesized as either monomeric or multiple antigenic (MAP) peptides. Abs to mouse La (mLa) developed faster and were of higher titer in mice immunized with the subdominant mLa25-44 MAP compared with mice immunized with the 25-44 monomer. Rapid intermolecular spreading of the autoimmune response to 60-kDa Ro was observed in AKR/J mice immunized with mLa25-44 MAP, but not in mice immunized repeatedly with monomeric peptide. A/J mice immunized and boosted with the known tolerogenic mLa287-301 determinant delivered as monomeric peptide failed to develop Abs to either intact mLa or mLa287-301 peptide. However, immunization with the multiva...
Science (New York, N.Y.), Jan 9, 2015
Human inborn errors of immunity mediated by the cytokines interleukin-17A/F (IL-17A/F) underlie m... more Human inborn errors of immunity mediated by the cytokines interleukin-17A/F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origens with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, or RORγT, or both.
Transplantation proceedings
Transgenic Mice and Mutants in MHC Research, 1990
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1996
Clustering of autoantibody specificities is a consistent finding in patients with systemic autoim... more Clustering of autoantibody specificities is a consistent finding in patients with systemic autoimmune diseases. Patients with Sjögren's syndrome frequently have autoantibodies to La, 60-kDa Ro(SS-A) protein (Ro60), and 52-kDa Ro(SS-A) protein (Ro52). In the case of anti-Ro60 and anti-La, there is evidence that these specificities occur together because of the physical association of the Ro60 and La proteins that form a ribonucleoprotein particle (RNP). Thus, the autoantibody response may spread from a single epitope to involve new epitopes located within other components of the RNP. The physical association of Ro52 with the Ro/La RNP has remained controversial, implying that Abs to Ro52 are not a consequence of intermolecular spreading and may be triggered independently of the anti-Ro60 response. To examine this relationship of the immune response to Ro52 and Ro60, mice were immunized with recombinant Ro52, Ro60, or La, and examined for autoantibody production. Immunization with...
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Papers by James McCluskey